US9504650B2 - Pharmaceutical composition containing vitamin B12 - Google Patents

Pharmaceutical composition containing vitamin B12 Download PDF

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Publication number
US9504650B2
US9504650B2 US14/647,914 US201314647914A US9504650B2 US 9504650 B2 US9504650 B2 US 9504650B2 US 201314647914 A US201314647914 A US 201314647914A US 9504650 B2 US9504650 B2 US 9504650B2
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vitamin
pharmaceutically acceptable
acceptable carrier
pharmaceutical composition
deficiency
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US14/647,914
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US20150306033A1 (en
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Klaas Alouis Riepma
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to a pharmaceutical composition for intranasal administration to a human subject comprising vitamin B12 and a pharmaceutically acceptable carrier.
  • Vitamin B12 is a vitamin that plays a role in mammalian growth, hematopoiesis, production of epithelial cells and maintenance of the nervous system. It is quite water-soluble and thus could be expected to be easily available to human subjects. However, the absorption from the gut of normal dietary amounts of vitamin B12 is believed to be dependent on gastric Intrinsic Factor (GIF), and the loss of Intrinsic Factor leads to vitamin B12 deficiency. The loss of ability to absorb vitamin B12 (B12) is the most common cause of adult B12 deficiency.
  • GIF gastric Intrinsic Factor
  • Such a loss may, for example, be due to pernicious anemia (with loss of Intrinsic Factor) or to a number of other conditions that decrease production of gastric acid, which also plays a part in absorption of B12 from foods. Deficiency is most significantly linked to inadequate absorption rather than low consumption, as those who consume high amounts of vitamin B12 may still experience deficiency as evidenced by a low blood concentration. Vitamin B12 deficiency results in various undesirable conditions such as fatigue, depression, poor memory, etc. [Source: Wikipedia].
  • vitamin B12 deficiency causes of vitamin B12 deficiency include atrophic gastritis (a thinning of the stomach lining), surgery in which part of the stomach and/or small intestine is removed, conditions affecting the small intestine (such as Crohn's disease, celiac disease, bacterial growth, or a parasite), excessive alcohol consumption, autoimmune disorders (such as Graves' disease or systemic lupus erythematosus) and drug abuse.
  • atrophic gastritis a thinning of the stomach lining
  • surgery in which part of the stomach and/or small intestine is removed conditions affecting the small intestine (such as Crohn's disease, celiac disease, bacterial growth, or a parasite)
  • autoimmune disorders such as Graves' disease or systemic lupus erythematosus
  • compositions containing vitamin B12 according to the preamble are known in the art, for example from U.S. Pat. No. 5,801,161 to Merkus, which discloses an intranasal spray. Such a pharmaceutical composition is brightly red, with as the concomitant disadvantage that any fluid of the pharmaceutical composition running from the nose will give the appearance of a bloody nose.
  • Further prior art includes i) Nascobal, a nasal solution of cyanocobalamin available in the USA, and ii) (Br. J. Clin. Pharmacol, 1998, January, 45(1): 83-86 to Asselt et al, showing that hydroxocobalamin nasal sprays are effective in treating vitamin B12 deficiency in elderly adults.
  • the object of the present invention is to provide a pharmaceutical composition for intranasal administration with good bioavailability of the active ingredient and with reduced colour intensity by vitamin B12.
  • a pharmaceutical composition according to the preamble is characterized in that vitamin B12 particles are dispersed in a hydrophobic continuous phase as the pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be in the form of an ointment, a nasal spray or nose drops.
  • the term vitamin B12 includes cyano-cobalamin, hydroxo-cobalamin, methyl-cobalamin, 5′-deoxyadenosyl-cobalamin, aquacobalamin, glutathionyl-cobalamin and nitrilocobalamin, including the pharmaceutically acceptable salts thereof.
  • the concentration of vitamin B12 in the pharmaceutical composition is between 0.01-25 wt./vol. %.
  • the pharmaceutically acceptable carrier is chosen from at least one of i) fat, ii) fatty acids, and iii) wax.
  • the fatty acids have a length of the carbon chain of at least 6.
  • pharmaceutically acceptable carrier is oil.
  • Such a liquid pharmaceutical composition is convenient to administer and to result in high adsorption of vitamin B12 based on concentration in the blood of a human subject.
  • the pharmaceutically acceptable carrier is an anhydrous pharmaceutically acceptable carrier.
  • Anhydrous means within the context of the present invention means a water content of less than 5 wt./wt. %, preferably less than 1 wt./wt. % and more preferably with less than 0.2 wt./wt. %.
  • the pharmaceutical composition comprises methylcobalamin or a pharmaceutically acceptable salt thereof as vitamin B12.
  • Methylcobalamin is considered a powerful drug but because it decomposes easily this value has not been realized in intranasal pharmaceutical compositions according to the prior art as it can't be stored or pharmaceutical compositions have to be kept frozen.
  • the hydrophobic pharmaceutical composition according to the present invention will benefit from improved stability, in particular for methylcobalamin.
  • the concentration of vitamin B12 is in the range of 0.05-10 wt./vol. % preferably between 0.4-8 wt./vol. %.
  • a typical concentration will be, for example, 1000 ⁇ g per dose of 100 ⁇ l.
  • the amount administered to a nose will be 50-150 ⁇ l of the pharmaceutical composition per nostril, as more would run out of the nose and not be effective.
  • vitamin B12 is colloidally dispersed.
  • Such a pharmaceutical composition is stable for longer periods.
  • the present invention also relates to vitamin B12 dispersed in a hydrophobic continuous phase, for use in the intranasal treatment of vitamin B12 deficiency.
  • It may be a condition chosen from autism spectrum disorder, fatigue, memory deficiency, ALS, Alzheimer, deficiency caused by drug abuse, thinning of the stomach lining, vitamin B12 deficiency after surgery in which part of the stomach and/or small intestine is removed, Crohn's disease, celiac disease, Graves' disease, systemic lupus erythematosus and migraine.
  • the present invention relates to a method of treating a human subject suffering from a condition chosen from autism spectrum disorder, fatigue, memory deficiency, ALS, Alzheimer, deficiency caused by drug abuse, thinning of the stomach lining, vitamin B12 deficiency after surgery in which part of the stomach and/or small intestine is removed, Crohn's disease, celiac disease, Graves' disease, systemic lupus erythematosus and migraine, wherein a pharmaceutical composition according to any of the claims 1 to 7 is administered intranasally.
  • a condition chosen from autism spectrum disorder, fatigue, memory deficiency, ALS, Alzheimer, deficiency caused by drug abuse, thinning of the stomach lining, vitamin B12 deficiency after surgery in which part of the stomach and/or small intestine is removed, Crohn's disease, celiac disease, Graves' disease, systemic lupus erythematosus and migraine, wherein a pharmaceutical composition according to any of the claims 1 to
  • the method avoids what would appear like a bloody nose due to the intense red colour of vitamin B12.
  • FIG. 1 shows a graph with experimental data after administration of a nasal dose of a pharmaceutical composition according to the invention.
  • FIGS. 2 a to 2 c show HPLC chromatograms of a stability experiment with methylcobalamin.
  • the stability of methylcobalamin is sesame oil was investigated, using an aqueous solution as a control.
  • the assay was performed as disclosed in the Japanese Pharmacopoeia Ed. XV (page 844-845), using octasulphonic acid as eluent. A freshly prepared solution was used as the standard, which resulted in two peaks (after 8′ and 32′), as shown in FIG. 2 a . The control resulted in a main peak at 14.5′, none after 32′ ( FIG. 2 b ). Methylcobalamin stored in sesame oil resulted in a chromatogram identical to the standard ( FIG. 2 c ).
  • Cyanocobalamin was reduced in size using a pestle and mortar.
  • a suspension was prepared in sesame-oil in a concentration of 1500 ⁇ g per 100 microliter.
  • Subject A received a total dose of 200 ⁇ l.
  • Subject B received the same amount of sesame oil without Cyanocobalamin. Blood samples were taken at times 0, and every hour after inhalation. Vitamin B12 was measured using a competitive enzyme immunoassay method.
  • FIG. 1 These data are graphically presented in FIG. 1 . As can be seen in the figure the concentration increased up to almost 3000 pmol/l. Such a high concentration is believed not to have been reported in the literature before for the nasal absorption of cyanocobalamin. Next to none red fluid was discharged from the nose after administration to subject A. Both the pharmaceutical composition and the control were tolerated well by both subjects.
  • Example 2 The experiment of Example 1 was repeated with hydroxo-cobalamin HCl. A suspension was prepared of 1.5% by w/v hydroxocobalamine in sesame oil. A male subject (52 years) received a single droplet of this suspension in each nostril, and then inhaled. Total amount 200 ⁇ l.
  • the blood level was 21070 pmol/l, compared to 900 pmol/l immediately before administration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Nutrition Science (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US14/647,914 2012-11-30 2013-11-28 Pharmaceutical composition containing vitamin B12 Expired - Fee Related US9504650B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
NL2009918 2012-11-30
NL2009918 2012-11-30
NL2010550 2013-03-30
NL2010550A NL2010550C2 (en) 2012-11-30 2013-03-30 An intranasal pharmaceutical composition containing vitamin b12.
PCT/NL2013/050860 WO2014084736A1 (en) 2012-11-30 2013-11-28 A pharmaceutical composition containing vitamin b12

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US20150306033A1 US20150306033A1 (en) 2015-10-29
US9504650B2 true US9504650B2 (en) 2016-11-29

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US (1) US9504650B2 (pl)
EP (1) EP2925294B1 (pl)
CN (1) CN104955442B (pl)
AU (1) AU2013352633B2 (pl)
BR (1) BR112015012281A2 (pl)
CA (1) CA2893003C (pl)
DK (1) DK2925294T3 (pl)
ES (1) ES2690403T3 (pl)
IL (1) IL239064A (pl)
LT (1) LT2925294T (pl)
MY (1) MY170475A (pl)
NL (1) NL2010550C2 (pl)
PL (1) PL2925294T4 (pl)
PT (1) PT2925294T (pl)
RS (1) RS57698B1 (pl)
RU (1) RU2655696C2 (pl)
SI (1) SI2925294T1 (pl)
WO (1) WO2014084736A1 (pl)

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Publication number Priority date Publication date Assignee Title
NL2015506B1 (en) * 2015-09-25 2017-04-20 Alouis Riepma Klaas Oral administration of Vitamin B12 dispersed in a hydrophobic continuous phase
CN110916192B (zh) * 2019-11-25 2021-04-13 垒途智能教科技术研究院江苏有限公司 一种具有防治儿童青少年自闭症的益生菌矿物粉及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0735859B1 (en) 1993-12-20 1997-07-30 Franciscus Wilhelmus Henricus Maria Merkus A pharmaceutical composition for the intranasal administration of hydroxocobalamin
US20020022052A1 (en) 2000-04-06 2002-02-21 Dransfield Charles William Transdermal delivery system
WO2007022345A2 (en) 2005-08-17 2007-02-22 Fleming And Company, Pharmaceuticals Vitamin b12 nasal spray and method of use
US20120157536A1 (en) * 2010-12-20 2012-06-21 Polytherapeutics, Inc. Composition for transdermal administration of non-steroidal anti-flammatory drug

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0647717A1 (en) * 1993-10-06 1995-04-12 Takeda Chemical Industries, Ltd. Method of producing vitamin B12
US20020022505A1 (en) * 2000-08-15 2002-02-21 Freeburn James Henry Circumferential thresher
CZ2003808A3 (cs) * 2000-09-20 2003-08-13 Nycomed Pharma As Způsob výroby prostředku ve formě kapalné emulse
DE202004015931U1 (de) * 2004-10-13 2005-01-05 Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh Omega-3-Fettsäuren und Omega-6-Fettsäuren enthaltende Zusammensetzung
US20060120967A1 (en) * 2004-12-07 2006-06-08 Qpharma, Llc Solution forms of cyclodextrins for nasal or throat delivery of essential oils

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0735859B1 (en) 1993-12-20 1997-07-30 Franciscus Wilhelmus Henricus Maria Merkus A pharmaceutical composition for the intranasal administration of hydroxocobalamin
US5801161A (en) 1993-12-20 1998-09-01 Merkus; Franciscus W. H. M. Pharmaceutical composition for the intranasal administration of hydroxocobalamin
US20020022052A1 (en) 2000-04-06 2002-02-21 Dransfield Charles William Transdermal delivery system
WO2007022345A2 (en) 2005-08-17 2007-02-22 Fleming And Company, Pharmaceuticals Vitamin b12 nasal spray and method of use
US20120157536A1 (en) * 2010-12-20 2012-06-21 Polytherapeutics, Inc. Composition for transdermal administration of non-steroidal anti-flammatory drug

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
D.Z.B. van Asselt, et al., "Nasal Absorption of Hydroxocobalamin in Healthy Elderly Adults", Br J Clin Pharmacal, 45, 1998, pp. 83-86.
How to Use Nose Drops, Internet article, patient.info/health/how-to-use-nose-drops, Oct. 18, 2013. *
M.E. Aulton, Pharmaceutics, "The Science of Dosage Form Design"; p. 265; 1988.
Pray, Preventing and Treating Cold Sores, US Pharmacist 2007; 32(4): 16-23. *

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WO2014084736A1 (en) 2014-06-05
SI2925294T1 (sl) 2019-01-31
EP2925294A1 (en) 2015-10-07
CA2893003A1 (en) 2014-06-05
PL2925294T4 (pl) 2019-03-29
NL2010550C2 (en) 2014-06-04
BR112015012281A2 (pt) 2017-07-11
ES2690403T3 (es) 2018-11-20
RS57698B1 (sr) 2018-12-31
US20150306033A1 (en) 2015-10-29
MY170475A (en) 2019-08-06
CN104955442B (zh) 2018-01-30
RU2655696C2 (ru) 2018-05-29
IL239064A0 (en) 2015-07-30
PT2925294T (pt) 2018-10-26
AU2013352633B2 (en) 2017-09-28
EP2925294B1 (en) 2018-06-27
RU2015125681A (ru) 2017-01-10
IL239064A (en) 2016-06-30
DK2925294T3 (en) 2018-10-15
AU2013352633A1 (en) 2015-07-02
PL2925294T3 (pl) 2018-11-30
CN104955442A (zh) 2015-09-30
LT2925294T (lt) 2018-10-25
HK1210411A1 (zh) 2016-04-22
CA2893003C (en) 2016-11-01

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